Ghrelin is an orexigenic peptide involved in the regulation of energy homeostasis. To investigate the role of ghrelin in the hyperphagia associated with uncontrolled streptozotocin-induced diabetes, food intake was followed in diabetic: a) ghrelin knockout (ghrelin^-) and control wild-type (ghrelin^+/+) mice, b) NMRI mice treated with either saline or the ghrelin receptor antagonist, D-Lys³-GHRP-6 for 5 days,.

In diabetic ghrelin^- mice the hyperphagia was attenuated and the maximal increase in food intake was 50% lower in the mutant than in the wild-type mice. The increased food intake observed during the light period (10-12 am) in ghrelin^+/+ mice was abolished in the mutant mice. Diabetic ghrelin^- mice lost 12.4% more body weight than ghrelin^+/+ mice. In diabetic ghrelin^+/+ mice, the number of NPY IR-neurons was significantly increased but not in ghrelin^- mice.

Diabetic NMRI mice were hyperphagic and had increased plasma ghrelin levels. Treatment with D-Lys³-GHRP-6 reduced daily food intake by 23% and reversed the increased food intake observed during the light period. The change in the number of NPY (2.4 fold increase) and -MSH (1.7 fold decrease) immunoreactive (IR) hypothalamic neurons induced by diabetes was normalized by D-Lys³-GHRP-6 treatment. Our results suggest that enhanced NPY and reduced -MSH expression are secondary to the release of ghrelin which should be considered as the underlying trigger in the hyperphagia associated with uncontrolled diabetes.